6-1H-imidazo-quinazoline and quinolines derivatives, new potent analgesics and anti-inflammatory agents

ABSTRACT

The present invention is directed to novel 6-1H-imidazo-2-aryl and 2-heteroaryl quinazoline and quinoline of formula I, corresponding salts and solvates thereof, to a process for their preparation and to the use of this compounds and corresponding pharmaceutical composition for the treatment of pain and inflammatory related disorders. Compounds of the invention have been proven highly effective in the pharmacological treatment of both inflammatory and neuropathic pain, in addition to striking anti-inflammatory properties. Their effectiveness in interfering with COX-2 and inflammatory cytokines expressions and production, highlights them as interesting compounds also for the treatment of cancer in addition to several inflammatory diseases. 
     Formula I:

The present invention is directed to novel 6-1H-imidazo-2-aryl and2-heteroaryl quinazoline and quinolines, to a process for theirpreparation, to their pharmaceutical compositions and to the use of suchcompounds and their pharmaceutical compositions for the treatment ofpain and inflammatory related disorders.

BACKGROUND

The conversion of arachidonic acid to prostaglandins and othereicosanoids is controlled by the two well known cyclooxygenase (COX)isoforms COX-1 and COX-2. COX-2 is an inducible isoenzyme that can beup-regulated in numerous pathologic conditions, including inflammationand cancer. Blocking COX activities with non steroidal anti-inflammatorydrugs (NSAIDs) is a widely adopted clinical strategy for the treatmentof inflammatory related diseases and pain. Main adverse-effectsassociated with the chronic usage of classical NSAIDs, aregastrointestinal serious side-effects and renal toxicity. SelectiveCOX-2 inhibitors, though lacking for the great part the gastrointestinaltoxicity typical of classical NSAIDs, have recently highlightedundesirable cardiovascular life threatening adverse-effects. Analternative to NSAIDs is the use of corticosteroids, however also inthis case chronic use can result in severe side effects.

Since approaches that target gene transcription may complement or evenbe more successful than the enzyme inhibition, exploration of strategiesto specifically block COX gene expression was the object of a remarkablescientific efforts in the last decade (R. G. Ramsay, Int. J.Immunopathol. Pharmacol., 2003, 16 (2S), 59-67). Recently, it wasreported that some NSAIDs (including Celecoxib) exert part of theiraction directly on COX-2 transcriptional regulation, explaining why suchagents display greater effects on this isoform than enzyme inhibitiondata would suggest (K. S. Chun, Biochem. Pharmacol. 2004, 68, 1089).Up-regulation of COX-2 is mediated by a variety of stimuli includingcytokines, tumour promoters, oncogenes and growth factors. Intracellularsignalling pathways which can induce and regulate COX-2 expressions arecomplex, and due to cell system dependence are still poorly understood.However, growing evidences suggests that IL-1β and COX-2 play a crucialrole in the pathogenesis of inflammatory diseases and tumour growth. Inthe most of tissues, IL-1β induced COX-2 over-expression is mediated bystimulation of either protein kinase C(PKC) or Ras signal transductionsystem which enhances mitogen-activated protein kinase (MAPK) activity,which in turn activates transcription of COX-2 along with othercytokines. It has been recently demonstrated, in several tissues, thatthe three MAP kinases (p38, JNK and ERK ½) are involved in controllingCOX-2 expression and translation. For instance, this was reported forhuman chondrocytes stimulated with IL-1β (N. Nieminen Mediators ofinflammation, 2005, 5, 249-255), or in human colorectal cancer cellsstimulated with IL-1β (W. Liu, Cancer Research, 2003, 63, 3632; CellularSignalling, 2006, 18, 1262), and in renal mesangial cells (J. Biol.Chem. 1998, 273, 28670).

Rheumatoid arthritis (RA) is a systemic inflammatory diseasecharacterized by articular synovitis leading to cartilage degradationand bone erosion. Rheumatoid synovium shows over expression of COX-2which in turn give rise to massive production of PGE₂, responsible forvasodilatation, fluid extravasations and pain. Among a variety ofmediators affecting COX-2 expression IL-1β appears to be the maintriggering agent (Arthritis Research, 2005, 57).

Osteoarthritis (OA) is the most common form of arthritis, and is largelyrecognized to be a frequent cause of serious disability in older adults.Synovial inflammation characterized by mononuclear cell infiltration,proliferation of new blood vessels, production of pro-inflammatorycytokines and other mediators of joint damage has been highlighted inthe synovial tissues from patients with early and late OA (Ann Rheum.Dis., 2005, 64, 1263-67), and the importance of synovitis in thepathophysiology of OA is increasingly recognized (Haywood, ArthritisRheum., 2003, 48, 2173; Shibakawa, Osteoarthritis Cartilage, 2003, 11,133). Increased expression of cytokines, COX-2, adhesion molecules andangiogenic factors are characteristics of chronic synovitis. It has beenshown how PGE₂ produced by COX-2, in human osteoarthritis explantsmodulates cartilage proteoglycan degradation, thus highlighting to thisinflammatory mediator not only a role in propagating the inflammationprocess but also a direct involvement in tissue degeneration (ArthritisRheum., 2002, 46, 1789). It has also been demonstrated how, in OAsynoviocytes the mechanism of IL-1β induction for COX-2 expressionsfollows the same signalling pathway above discussed for the chondrocytes(Arthritis & Rheum., 2004, 50, 2829).

Elevated levels of COX-2 expression have been detected along with highlevels of IL-1β, in patients affected by inflammatory bowel disease(IBD), Crohn's disease and ulcerative colitis, where theinflammatory/autoimmune response is triggered by an exaggerated responseto antigens produced by the gut bacteria.

Expression of COX-2 has been reported to be elevated in human colorectaladenocarcinoma and other tumors, including those of breast, cervical,prostate and lung. Genetic knock-out or pharmacological inhibition ofboth COX-2 and/or its expression has been proven to protect againstexperimentally-induced carcinogenesis. Accordingly, the inhibition ofabnormally or improperly elevated levels of COX-2, by blocking theenzyme and/or its expression, provides also one of the most effectiveand promising strategies for cancer chemoprevention.

Blockage of cytokines in inflammatory diseases, has lead to the greatestadvances in medicine of recent years. Tumor necrosis factor (TNF),interleukin-1 (IL-1) and interleukin-6 (IL-6) are important biologicalentities collectively referred to as pro-inflammatory cytokines, whichplay a role in several diseases, for example such as toxic shocksyndrome, RA, OA, diabetes and IBD. In these diseases, chronic elevationof inflammation exacerbates or causes much of the observedpathophysiology. Pro-inflammatory cytokines play a decisive role in thegeneration of the inflammatory and destructive cartilage degeneration aswell as bone erosion in arthritis (B. Moller, Springer Semin.Immunopathol., 2006, 391). Due to resulting structural damage, boneerosion is a major reason for disability in arthritis patients. Boneerosion in arthritis is a consequence of synovial osteoclast formation(B F. Boyce, Curr. opinion Rheumatol, 2006, 18, 427). Inflammatorycytokines produced in inflamed synovium induce in the bone marrow therelease of osteoclast precursors, which reached the inflamed joints andin response to cytokine stimuli differentiate into the bone-resorbingosteoclasts. Thus, pro-inflammatory cytokines in arthritis areresponsible for both the progression and diffusion of the inflammatorystatus within the joint as well as the bone damage. Antagonists of IL-1βhave been shown to reduce the degradation of cartilage matrix componentsin a variety of experimental models of arthritis. Interleukin-6 (IL-6)is a pro-inflammatory cytokine, prevalently expressed in activatedmonocytes and macrophages, which plays a fundamental role in manychronic inflammatory diseases, particularly implicated in the acutephase response and critically involved in the maintenance of the diseasestate (J. Scheller, Scand. J. Immunol., 2006, 63, 321). Overexpressionof IL-6 has been implicated in the pathology of IBD, arthritis (RA andOA), asthma, colon cancer, multiple myeloma, post-menopausalosteoporosis.

A number of anti-cytokines therapies are currently in clinical trials,and several monoclonal antibodies against TNF and recombinant solubleTNF receptor (Etanercept, Enbrel) as well as recombinant soluble IL-1receptor (Anakinra, Kineret) reached the market, demonstrating apronounced activity in treating diseases such as RA, IBD and Crohn'sdisease. These biological high-molecular weight products, which arebased on the antagonism of the circulating cytokine, are howeverexpensive, limited to parenteral administration route and can give riseto immunogenic adverse effects, likely due to their biological nature.

Strategies aimed at blocking cytokine production with small moleculesare still of great therapeutic interest, since could be more efficientin blocking cytokine circulation, not endowed with the immunogenicadverse effect of the biological product, less expensive and of simpleradministration route. In addition, simultaneous blockade of COX-2production and pro-inflammatory cytokines production should interruptthe self propagating loop which has been found relevant for thetriggering and maintenance of the pathology in inflammatory diseases.

As discussed above, inflammation causes the induction of COX-2, leadingto the release of prostanoids, which sensitize peripheral nociceptorterminals and produce localized pain hypersensitivity, howeverperipheral inflammation also generates central sensitization by directwidespread induction of COX-2 expression in spinal cord and CNS neurons,which results in an increased neuronal excitability and painhypersensitivity (J. Neurochem., 2003, 86, 318).

Although arthritis (OA and RA) is defined as inflammation of the joints,the primary feature with which patients present in the clinic is chronicpain; even though arthritis is not the only pathology which can giverise to chronic pain, it is rather common and quite representative ofthis kind of pain. Chronic pain can be divided into inflammatory pain, akind of pain more related to peripheral tissue damage/inflammation, andneuropathic pain. Neuropathic pain refers clinically to a group ofchronic pain syndromes. These syndromes share the common feature thatthey are caused by an initial nerve damage, which subsequently resultsin an abnormal sensory processing in the central and peripheral nervoussystem. Neuropathic pain conditions are the consequence of a number ofdiseases, for instance diabetes, cancer, amputees, multiple sclerosis.

Peripheral sensitization and central sensitization are the two majormechanisms underlying the generation of pain. When tissue damage occurs,mechanisms in both the nervous and the immune system trigger the releaseof sensitizing agents such as pro-inflammatory prostaglandins (PGE₂),5-HT, bradykinin, histamine, ATP, cytokines from inflammatory cells andnerve terminals. These mediators evoke activation of specific ionchannels through the excitation of peripheral nociceptive neurons,involving activation of intracellular kinases, and resulting inperipheral sensitization. Activation of peripheral nociceptors alsoreflects in a dependent neuronal plasticity in the CNS. This plasticitymodifies the performance of nociceptive pathway by enhancing andprolonging the responses to subsequent peripheral stimuli. These changesin the spinal cord, as well as in the brain are referred to centralsensitization. Central sensitization plays a major role in maintainingelevated pain sensitivity and it is responsible for the pain producedafter injury by normally innocuous low threshold afferent inputs. A socomplex mechanism for pain induction and control can explain why thetreatment of pain conditions has not found yet a satisfactorypharmacological solution.

In order to identify effective agents for the clinical management ofpain, several alternate pharmacological approaches have been carried outin the last decade, for example COX-2 inhibitors, displayed a goodefficacy in the treatment of inflammatory pain, but lacked effectivenessin the treatment of neuropathic pain, in addition for COX-2 inhibitorsthe undesirable life threatening side-effects mentioned above suggestnot to use these drugs for clinical management of chronic pain. Theavailable analgesics for the treatment of neuropathic pain, for instancesome tricyclic antidepressant (e.g.: Amitriptyline) and a fewantiepileptic drugs (e.g. gabapentin, lamotrigine, and carabamazepine)are effective in some patients, however there is still a large need forefficient drugs for neuropathic pain treatment.

Pharmacological agents acting at controlling cytokines and PGE₂expression can counteract the above described mechanisms of peripheraland central sensitization thus acting as efficient and potent analgesics(M. Schafer, Immune Mechanisms of Pain and Analgesia, pg. 41-50 PlenumPublishers, 2003).

DESCRIPTION OF THE INVENTION

The present invention comprises a new class of compounds, 6-1H-imidazolederivatives of 2-aryl and heteroaryl quinazolines and quinolines ofFormula (I), useful for the pharmacological treatment of inflammatorydiseases such as arthritis, typically rheumatoid arthritis andosteoarthritis, asthma and inflammatory diseases of the respiratorytract, chronic obstructive pulmonary disease (COPD), systemic lupuserythematosus, skin diseases such as eczema, psoriasis and dermatitis,gastrointestinal serious inflammatory conditions such as inflammatorybowel disease (IBD), ulcerative colitis, Crohn's disease (CD), postoperative inflammatory complications, and cancer including but notlimited to: colon cancer, multiple myeloma, breast, cervical, prostateand lung cancer. In addition compounds of the invention act as potentanalgesics, independently upon the pain was inflammatory pain orneuropathic pain. Accordingly, the compounds of the invention are usefulfor the treatment of both acute and chronic pain, including but notlimited to: postoperative pain, muscular pain, pain resulting fromvarious forms of trauma, as well as chronic pain, neuropathic pain,cancer pain, pain caused by arthritis and visceral pain.

wherein:

-   -   X is independently selected from a carbon or a nitrogen atom;    -   W is independently selected from an aryl group or an heteroaryl        group of Formula II:

-   -   when W is an aryl group, it is intended an unsubstituted or        substituted phenyl, with one or more substituents independently        selected from halogen (—F, —Cl, —Br), trifluoromethyl (—CF₃),        alkyl (—R₂), hydroxyl (—OH), alkoxy (—OR₃), trifluoromethoxy        (—OCF₃), cyano (—CN), carboxamido (—CONHR₃ or —NHCOR₃ or        —CONR₂R₃ or —NHCOR₃), carbonyl (—CO—R₃), alkylthio (—SR₃),        sulfinyl (—SOR₃) and sulfonyl (—SO₂R₃);    -   when W is an heteroaryl group of Formula II, it is a        benzocondensed -5 or -6 membered heterocycle, wherein:    -   Z and Y are independently selected from: an oxygen atom (—O—), a        sulphur atom (—S—), or the groups: —SO₂—, —CHR₃—, —CR₃═, —NH—,        —N═;    -   Q is independently selected from the groups: —CHR₃—, —CH═,        —CR₃═, —CHR₃—CH₂—;        provided that the combination of Y, Z, Q groups give rise to:        1,3-benzodioxole, 1,3-benzodithiol, benzofuran,        2,3-dihydrobenzofuran, benzothiophene,        2,3-dihydrobenzothiophene, 2,3-dihydrobenzothiophene        S,S-dioxide, indole, 2,3-dihydroindole, benzimidazole,        benzoxazole, benzothiazole, 2H-3,4-dihydrobenzopyran,        2H-3,4-dihydrobenzothiopyran, 2H-3,4-dihydrobenzothiopyran        S,S-dioxide, [1,4]-benzodioxine, 2,3-dihydro-[1,4]-benzodioxine        (1,4-benzodioxan), 1,4-benzothiazine,        2,3-dihydro-[1,4]-benzothiazine, 2,3-dihydro-[1,4]-benzothiazine        S,S-dioxide, [1,4]-benzoxazine, 2,3-dihydro-[1,4]-benzoxazine;    -   R₁ is independently selected from hydrogen (—H) or C₁-C₄ alkyl        or hydroxymethyl (—CH₂OH), aminomethyl (—CH₂NH₂),        dimethylaminomethyl (—CH₂NMe₂), trifluoromethyl (—CF₃); the        C₁-C₄ alkyl group is a linear or branched hydrocarbon chain;        provided that in compounds of formula I not more than two R1        groups are simultaneously C₁-C₄ alkyl or trifluoromethyl (—CF₃)        and only one R1 group is hydroxymethyl (—CH₂OH), aminomethyl        (—CH₂NH₂) or dimethylaminomethyl (—CH₂NMe₂);    -   R₂ is independently selected from C₁-C₆ alkyl or aryl; for C₁-C₆        alkyl herein is intended a linear or branched, saturated or        unsaturated C₁-C₆ hydrocarbon chain optionally substituted with        an aryl, aryl being herein intended as defined above;    -   R₃ is independently selected from hydrogen, C₁-C₆ alkyl and        aryl. For C₁-C₆ alkyl herein is intended a linear or branched,        saturated or unsaturated C₁-C₆ hydrocarbon chain optionally        substituted with an aryl, aryl being herein intended as defined        above.

According to this invention the compounds of Formula (I) may be used asthe free base or as a pharmaceutically acceptable salt thereof, or as asolvate or hydrate form of such salt.

The salts of the compounds of Formula (I) are pharmaceuticallyacceptable addition salts with inorganic and organic acids.Representative not limiting examples of inorganic salts are:hydrochloride, hydrobromide, hydrogensulphate and sulphate.Representative not limiting examples of organic salts are: maleate,fumarate, oxalate, methanesulfonate, succinate, ascorbate, tartrate.

In another embodiment this invention provides methods for thepreparation of compounds of Formula (I).

In a further embodiment this invention provides pharmaceuticalcompositions for compounds of Formula (I), useful for the treatment ofpain and inflammatory disorders as discussed above. Within the scope ofthe present invention the term pharmaceutical composition (drug product)refers to any oral, parenteral or topical dosage form, suitable for thetreatment of the above pathologies, that contains an effective amount ofat least one of the active pharmaceutical ingredients (drug substances),compounds of Formula (I), its salts or solvates thereof, and apharmaceutically acceptable carrier, excipients or diluents as definedbelow, for oral, parenteral or topic administration.

Representative not limiting examples of compounds of Formula (I) arelisted in Table 1.

TABLE 1 Name Structure MW Example [2-phenyl-6-(1H-imidazol-1-yl)]quinazoline

272.31 1 [2-phenyl-6-(1H-imidazol-1-yl)] quinoline

271.32 2 [2-(1,3-benzodioxol-5-yl)-6-(1H- imidazol-1-yl)]quinazoline

316.32 3 [2-(benzofuran-5-yl)-6-(1H- imidazol-1-yl)] quinazolinedihydrochloiride

385.25 4 [2-(2,3-dihydro-1,4-benzodioxin-6- yl)-6-(1H-imidazol-1-yl)quinazoline

330.35 5 [2-(3,4-dichlorophenyl)-6-(1H- imidazol-1-yl)]quinazoline

341.20 6 [2-[(4-benzyloxy)phenyl-6-(1H- imidazol-1-yl)] quinazolinedihydrochloride

451.36 7 [2-(4-chlorophenyl)-6- (1H-imidazol-1-yl)] quinazoline

306.76 — [2-(4-fluorophenyl)-6-(1H- imidazol-1-yl)] quinazoline

290.30 — [2-(3,4-difluorophenyl)-6-(1H- imidazol-1-yl)] quinazoline

308.29 — [2-(4-methoxyphenyl)-6-(1H- imidazol-1-yl)]quinazoline

302.34 — [2-(2,3-dihydro-benzofuran-5-yl)-6-(1H-imidazol-1-yl)]quinazoline

314.35 — [2-(benzoxazol-5-yl)-6-(1H- imidazol-1-yl)]quinazoline

313.32 — [2-(2H-3,4-dihydro-1-benzopyran- 6-yl)-6-(1H-imidazol-1-yl)]quinazoline

328.38 — N-[2-(2,4-dihydro-benzothiophen-1,1-dioxide-5-yl)-6-(1H-imidazol- 1-yl)]quinazoline

362.41 — [2-(4-fluorophenyl)-6-(1H- imidazol-1-yl)]quinoline

289.31 — [2-(3,4-difluorophenyl)-6-(1H- imidazol-1-yl)]quinoline

307.31 — [2-(4-methoxyphenyl)-6-(1H- imidazol-1-yl)]quinoline

302.34 — [2-(2,3-benzodioxol-5-yl)-6-(1H- imidazol-1-yl)]quinoline

315.33 — [2-(benzoxazol-5-yl)-6-(1H- imidazol-1-yl)]quinoline

312.33 — [2-(2,3-dihydro-benzofuran-5-yl)-6-(1H-imidazol-1-yl)]quinoline

316.36 — [2-(benzofuran-5-yl)-6-(1H- imidazol-1-yl)]quinoline

311.35 — [2-(2H-3,4-dihydro-1-benzopyran- 6-yl)-6-(1H-imidazol-1-yl)]quinoline

327.39 — [2-[(4-benzyloxy)phenyl-6- (1H-imidazol-1-yl)]] quinoline

377.45 — [2-[(4-phenyloxy)phenyl-6- (1H-imidazol-l-yl)]] quinoline

363.42 — [2-[(4-fluorophenyloxy)phenyl-6- (1H-imidazol-1-yl)]] quinoline

381.41 — [2-[(4-fluorophenyloxy)phenyl-6- (2-methyl-1H-imidazol-1-yl)]]quinoline

395.44 — [2-(1,3-benzodioxol-5-yl)-6- (2-methyl-1H-imidazol-1-yl)]quinazoline

330.35 — [2-(1,3-benzodioxol-5-yl)-6- (4-methyl-1H-imidazol-1-yl)]quinazoline

330.35 — [2-(1,3-benzodioxol-5-yl)-6- (4-methyl-1H-imidazol-1-yl)]quinoline

329.36 —

Preparation of the Compounds of the Invention

Compounds of Formula (I) can be prepared by reacting a compound ofFormula III with an imidazole derivative of Formula (IV) as depicted inScheme 1, wherein X, W and R₁ have the same meanings as discussed abovefor compounds of Formula (I) and Hal is an halogen atom such asfluorine, chlorine, bromine and iodine, typically bromine and iodine.

The reaction of a compound of Formula III can be carried out using animidazole derivative of Formula IV as free base or its alkaline metalsalt (sodium, lithium or potassium salt), in the presence of a suitablecatalyst, in a solvent such as dimethylformamide (DMF),dimethylsulfoxide (DMSO), acetonitrile, N-methylpyrrolidone (NMP),dimethoxyethane, tetrahydrofurane (THF), toluene or xylene, at atemperature ranging from 50° C. to 200° C.

Reaction of imidazole derivatives of formula IV with aryl halides offormula III can be carried out for example, in the presence of coppercatalyst (CuI), using potassium carbonate or cesium carbonate as base,in DMF at 100° C., as reported for other substrates (J. Med. Chem.,2002, 45, 1697-1711). Alternatively, a mixture of Cu/CuO can be used ascatalyst, in a DMSO-toluene mixture (Chem. Comm., 2004, 7, 778-779).Reaction of imidazole derivatives of formula IV, wherein R1 in position2 is alkyl, with aryl halides of formula III can be carried out usingtriethylammonium carbonate as base, CuI as catalyst, 8-hydroxyquinolineas ligand in a mixture DMF-water as solvent, as reported for othersubstrates (J. Org. Chem., 2005, 70, 10135). Compounds of formula I,wherein R1 in position 4 is alkyl or hydroxymethyl, can be easilyobtained by reacting compounds of formula IV, wherein R1 in position 5is alkyl or hydroxymethyl, with the halide of formula IV using CuI ascatalyst, Cs₂CO₃ as base and DMF as solvent as reported for othersubstrates (J. Org. Chem. 2004, 69, 5578; Bioorg. Med. Chem. Lett.,2003, 13, 3521). Compounds of formula I, wherein R1 in position 4 isaminomethyl or dimethylaminomethyl can be easily obtained usingprocedures similar to the ones described for other substrates (J. Med.Chem., 1987, 12, 2163-9; Synthesis, 1983, 1, 47-9).

Reaction of imidazole derivatives of formula IV with aryl halides offormula III can be carried out also using copper catalyst and the sodiumsalt of the derivative of formula IV, analogously to the literature(Bioorg. Med. Chem., 2004, 12, 2251). The compounds of formula IV assodium salt are reacted with the aryl halide, in the presence ofcatalytic amounts of CuO, in DMF at 150° C. Alternatively, aryl bromidescan be transformed into the corresponding N-imidazolyl derivatives bytreating them with two equivalents of imidazole (as free base) in thepresence of copper bromide or iodide (10% mol) and potassium carbonatein NMP, under microwave irradiation (Terahedron Lett., 2003, 4217-4218).Buchwald et al. demonstrated that the N-arylation of imidazoles can beaccomplished in high yields and avoiding too drastic conditions, usingCu(OTf)₂.benzene complex as copper source and cesium carbonate as base,in the presence of 1,10-phenantroline and dba (dibenzylidene acetone) asadditives, in xylene at 110-125° C. (Tetrahedron Lett., 1999, 40, 2657);this methodology can be successfully applied for converting compounds offormula III into compounds of formula I. Catalyzed addition of imidazolederivatives of Formula IV to aryl halides of formula III can be alsocarried out using Palladium as catalyst, alone or in combination withcopper. The methodology of Buchwald-Hartwig for imidazole addition toaryl bromides, in DMF as solvent, using both Binap[2,2′-bis(diphenylphosphino)-1,1′-binaphtyl] or Dppf[1,3-bis(diphenylphosphino propane]palladium soluble catalysts, andpotassium tert-butylate as base under microwave heating (Y. Wan,Synthesis 2002, 11, 1597-1600), can be successfully extended to thepreparation of compounds of formula I starting from halides of formulaIII. Compounds of formula I where at least one of R1 substituents is atrifluoromethyl group can be prepared by N-arylation using analogueprocedures (J. Med. Chem., 1989, 32, 575).

Alternatively, a compound of Formula I can be prepared from a compoundof Formula V by reaction with glyoxal or a dicarbonyl derivative offormula VI in the presence of formaldehyde or of an aldehyde of formulaR₁CH(O) and ammonium chloride, as depicted in Scheme 2.

Wherein X, W and R₁ have the same meanings as discussed for compounds ofFormula (I).

The reaction is usually carried out in methanol or ethanol in thepresence of a suitable acid catalyst such as phosphoric acid. Compoundsof Formula I, where all R1 are hydrogen atoms, can be obtained insatisfactory yields by treating compounds of formula V with glyoxal, inmethanol, typically at room temperature, then adding NH₄Cl andformaldehyde, and heating at reflux, finally phosphoric acid is added.Compounds of Formula I bearing substituted imidazoles can be prepared bythe same procedure, but using a dicarbonyl compound of formula VI(wherein at least one R1 is not hydrogen) as described for othersubstrates (Synthesis, 2003, 2661-2666). Optionally, an aldehyde offormula R₁CHO can be used instead of formaldehyde.

Alternatively, a compound of Formula I, where R1 at position 2 and 5 ishydrogen, can be prepared from a compound of Formula V by reaction withthiophosgene, followed by addition and cyclization of the amine offormula (VII), the resulting imidazol-2-thione is then desulfurized tothe corresponding compound of Formula I as summarized in Scheme 3.

Wherein X, W and R₁ have the same meanings as reported for compounds ofFormula (I). The reaction involves the formation of a thiocyanate addingthiophosgene to an aqueous hydrochloric acid solution of the compound offormula V. The resulting isothiocyanate is reacted withaminoacetaldehyde dialkyl acetal (usually dimethyl or diethyl acetal) inalcohol as solvent, at the reflux temperature and in the presence of anorganic base. The resulting quinoline or quinazoline imidazol-2-thionederivative is treated with 20% nitric acid and heated at about 100° C.to provide compounds of Formula I. A milder procedure, involving the useof diluted nitric acid and sodium nitrite at temperatures not exceeding0° C., can be used for sensible compounds, according to Bioorg. & Med.Chem., 2004, 13, 363-386. Moreover, acid sensible2-thioimidazolyl-substituted quinoline or quinazoline derivatives can bedesulfurized to compounds of Formula I using nickel raney in alcoholicsolvents such as ethanol or methanol (Archiv. Der Pharmazie, 2002, 335,69-76), or H₂O₂ in acetic acid (J. Het. Chem., 2003, 40, 229), or usingH₂O₂ in the presence of a transition metal catalyst (Org. Process Res. &Dev., 2002, 674). Some variations in the preparation of the2-thioimidazolyl-substituted quinoline or quinazoline derivatives,applicable to the preparation of the several compounds of Formula I canbe carried out according to procedures reported in the literature forother substrates (Synthetic Commun. 1997, 27, 3565; Synthesis, 1987, 12,1136; Synthesis 1978, 10, 741).

Alternatively, a compound of Formula I where X is a carbon atom, can beprepared from a compound of Formula VIII by reaction with a boronate offormula IX or IXa (scheme 4).

Compounds of Formula VIII can be prepared, according to Scheme 5, from acarbostiryl derivative of formula VIIIa. The carbostiryl derivative offormula VIIIa being prepared according to known methods from6-bromo-carbostiryl (Walker et al., U.S. Pat. No. 4,792,561, Dec. 20,1988). Appropriate reaction conditions for transforming VIIIa into VIIIare as described (Biochemistry, 2005, 44, 9637; Bioorg. Med. Chem.Lett., 2002, 12, 1361; Gazzetta Chimica It., 1989, 119, 163). Compoundsof formula IX and IXa are commercial compounds or can be prepared fromcommercial compounds according to standard procedures.

Compound of Formula III where the halogen atom is bromine can beobtained from compound of Formula V by diazotization in the presence ofHBr and CuBr, according to known methods (J. of Labelled Compounds,1991, 29, 415), as depicted in Scheme 6, wherein X and W have the samemeanings as discussed above for compounds of Formula (I). Aryl iodidescan be obtained by reaction of a compound of formula V with NaNO₂ andHCl in the presence of KI (J. Med. Chem., 2001, 15, 2391). Arylchlorides can be obtained by diazotization in the presence of CuCl (J.Het. Chem. 1991, 28, 1981). Compound of formula VIIIa can be obtainedfrom 6-bromocarbostiryl using analogue procedures as those described forScheme 1 (J. Med. Chem., 1989, 32, 1173).

Alternatively, when in compounds of Formula I X is nitrogen, compoundsof formula III can be obtained by reaction of acyl chlorides of formulaX or Xa with benzylamine derivatives of formula XI, followed bycyclization and aromatization as summarized in Scheme 7.

Wherein R₃, Y, Z, and Q have the same meanings as for compounds ofFormula (I). Compounds of formula XI are prepared according to knowmethods.

Not limiting representative examples for preparations of compounds ofFormula (I) are reported below.

Example 1 [2-phenyl-6-(1H-imidazol-1-yl)]quinazoline

To a solution of imidazole (1.53 g, 2.24 mmol) in DMF (3 ml), under N₂,was added NaH (60% dispersion in oil, 0.85 g, 2.2 mmol) portion wise,the mixture was stirred for 10 min at r.t. Then6-bromo-2-phenyl-quinazoline (2.0 g, 0.7 mmol) and CuO (0.19 g, 0.24mmol) were added, the mixture was heated at 150° C. for 6 h, cooled andpoured onto water. The precipitate was filtered, washed with water anddissolved in hot AcOEt/THF 1/1. The insoluble material was filtered offand the filtrate was concentrated. The obtained solid was trituratedwith diisopropyl ether and dried in vacuum (1.08 g, 57% yield).C₁₇H₁₂N₄; MW: 272.31; mp 153.8-158.7° C.; ¹H NMR (DMSO-d6) 9.72 (s, 1H),8.39-8.63 (m, 5H), 8.23 (d, 1H), 8.00 (s, 1H), 7.58-7.62 (m, 3H), 7.23(s, 1H); IR (KBr) 1556, 1506, 1379; TLC (CHCl₃:MeOH 9:1) Rf=0.50

6-bromo-2-phenyl-quinazoline

To a suspension of 5-bromo-2-amino-benzylamine dihydrochloride (38 g,0.138 mol) in dichloromethane (DCM) (1 l) was added at 0° C.triethylamine (TEA) (67.5 ml, 0.485 mol) and a solution of benzoylchloride (17 ml, 0.145 mol) in DCM (200 ml). The mixture was stirred for1 h at r.t. Water was added and the organic phase was separated, washedwith water and dried over Na₂SO₄. The solvent was removed in vacuum(i.v.) and the residue suspended in POCl₃ (200 ml). The mixture washeated at reflux for 1 hour, then the solvent was removed i.v., and theresidue partitioned between AcOEt and 0.1 N NaOH. The organic layer waswashed with 0.1 N NaOH and water, then dried over Na₂SO₄ andconcentrated i.v. to provide a solid. A mixture of the obtained solidand chloranil (35 g, 0.138 mol) in toluene (600 ml) was heated at refluxfor 4 hours. The mixture was concentrated i.v. and the residue wastreated with DCM. The insoluble was filtered off and washed with DCM.The combined filtrates were washed with 0.1 N NaOH and then with water.The solution was dried over Na₂SO₄ and concentrated i.v. The obtainedsolid was triturated with methanol and dried i.v. (22 g, 56% yield).C₁₄H₉BrN₂; MW: 285.15; ¹H NMR (DMSO-d6) 9.70 (s, 1H), 8.49-8.56 (m, 3H),8.17 (dd, 1H), 8.02 (d, 1H), 7.58-7.61 (m, 3H); TLC (AcOEt:PE 2:8)Rf=0.70.

5-bromo-2-amino-benzylamine dihydrochloride

A solution of borane in THF (1 M, 400 ml) was added at 0° C. to asuspension of 5-bromo-anthranilonitrile (60 g, 0.304 mol, prepared asdescribed in S. M. Mackenzie et al, J. Chem. Soc. C, 1970, 17,2298-2308) in THF (450 L), under N₂. The mixture was stirred for 72hours at r.t. After cooling at 0° C. absolute EtOH was added, then HClwas bubbled through the solution. The mixture was concentrated i.v.pressure and the residue was triturated with diisopropyl ether. Theobtained solid was dried i.v. to give the titled product (76.6 g, 91.4%yield). C₇H₉BrN₂. 2HCl, MW 273.9; ¹H NMR (DMSO-d6) 8.57 (s, 2H), 7.73(s, 1H), 7.55 (dd, 1H), 7.24 (d, 1H), 5.82 (s, 4H), 4.13 (s, 2H); TLC(CHCl₃:MeOH:H₂O:NH₃ 85:25:2:1) Rf=0.3.

Example 2 [2-phenyl-6-(1H-imidazol-1-yl)]quinoline

2-phenyl-6-amino-quinoline (1.0 g, 4.54 mmol) (prepared as described inEP1571142) dissolved in methanol (20 ml) was treated with 40% aq glyoxal(0.52 ml, 4.54 mmol) for 20 hours at r.t. NH₄Cl (486 mg, 9.08 mmol) wasadded followed by 37% aq. formaldehyde (0.68 ml, 9.08 mmol). The mixturewas diluted with methanol (200 ml) and refluxed for 1 hour. H₃PO₄ (0.64ml, 85%) was added over 10 minutes. The resulting mixture was thenstirred at reflux for a further 20 hours. After removal of the solvent,the dark residue was poured onto ice and neutralized with aq 30% NaOHuntil pH 9. The resulting mixture was extracted with Et₂O. The organicphases were combined and washed with water, brine and dried (Na₂SO₄).The solvent was removed and the residue was triturated with isopropylether to afford 700 mg (yield: 57%) of the titled product. C₁₈H₁₃N₃,M.W. 271.32. mp: 141.7-147.5° C., ¹H-NMR (d₆-DMSO): 8.52 (d, 1H);8.30-7.92 (m, 6H); 7.60-7.25 (m, 5H); 7.20 (s, 1H). MS: M⁺272; IR(KBr):3391, 3055, 1620, 1598, 1499 cm⁻¹. TLC: (9/1 chloroform/methanol)Rf=0.50.

Example 3 [2-(1,3-benzodioxol-5-yl)-6-(1H-imidazol-1-yl)]quinazoline

A suspension of 6-amino-2-(1,3-benzodioxol-5-yl)-quinazoline (2.5 g, 9.4mmol) and 40% aqueous glyoxal (1.1 ml, 9.4 mmol) in methanol (20 ml) wasstirred at r.t. for 18 h. NH₄Cl (1.0 g, 0.019 mol), 37% aqueousformaldehyde (1.4 ml, 19 mmol) and methanol (200 ml) were added and themixture was refluxed for 1 h. 85% H₃PO₄ (1.4 ml) was added and themixture was heated at reflux for a further 4 h. The solvent was removedand the residue was poured onto water, and basified with aq. NaOH. Theprecipitate was filtered, washed with water and dissolved in DCM. Theproduct was extracted with aqueous HCl (0.001 N) for three times. Theaqueous layers were collected, basified with Na₂CO₃ and extracted withchloroform. The organic layer was washed with water and dried overNa₂SO₄. The solution was concentrated i.v., and the residue wastriturated with diisopropyl ether. The solid was filtered and dried togive the titled product (2.0 g, 29% yield). C₁₈H₁₂N₄O₂, MW: 316.32. mp217-218° C.; ¹H NMR (DMSO-d6) 9.65 (s, 1H), 8.36-8.50 (m, 3H), 8.14-8.22(m, 2H), 8.00 (d, 2H), 7.21 (s, 1H), 7.12 (d, 1H), 6.16 (s, 2H); IR(KBr) 1504, 1446, 1251; TLC (CHCl₃:MeOH 9:1) Rf=0.30.

6-amino-2-(1,3-benzodioxol-5-yl)-quinazoline

A suspension of 6-nitro-2-(1,3-benzodioxol-5-yl)-quinazoline (37 g,0.126 mol) and SnCl₂ 2H₂O (117.2 g, 0.504 mol) in ethanol (500 ml) washeated at reflux for 1 h. After cooling to r. t., the solvent wasremoved i.v., chloroform was added and the mixture was basified withammonia. The precipitate was filtered off and washed with chloroform.The filtrates were collected, washed with water and dried over Na₂SO₄.The solution was concentrated i.v., and the residue triturated withdiisopropyl ether/petroleum ether. The solid was filtered and dried i.v.to give the titled product (21.2 g, 64% yield). C₁₅H₁₁N₃O₂, MW: 265.27.mp 191-192° C.; ¹H NMR (DMSO-d6) 9.24 (s, 1H), 8.05 (dd, 1H), 7.91 (d,1H), 7.73 (d, 1H), 7.39 (dd, 1H), 7.03 (d, 1H), 6.90 (d, 1H), 6.11 (s,2H), 5.93 (s, 2H); IR (KBr) 3319, 3203, 1631, 1500, 1446; TLC(CHCl₃/MeOH 9/1) Rf=0.3.

6-nitro-2-(1,3-benzodioxol-5-yl)-quinazoline

To a suspension of 5-nitro-2-amino-benzylamine hydrochloride (31 g,0.152 mol) in DCM (450 ml) was added at 0° C. TEA (52.6 ml, 0.38 mol)and a solution of piperonyloyl chloride (27.3 g, 0.16 mol) in DCM (80ml). The mixture was stirred for 2 hours at r.t. The solvent was removedi.v. and the residue triturated with ethanol/water 1/9, then withdiisopropyl ether. The obtained solid was dried and suspended in toluene(900 ml) and POCl₃ (670 ml). The mixture was heated at reflux for 2hours, then the solvent was removed i.v. and the residue was trituratedwith water/ammonia, washed with water, dried over P₂O₅. A mixture of theobtained product and chloranil (32.7 g, 0.129 mol) in toluene (500 ml)was heated at reflux for 2 hours. The mixture was concentrated i.v. andthe residue was triturated with NaOH 1M, washed with water and withmethanol. The obtained solid was dried i.v. (37 g, 82.5% yield).C₁₅H₉N₃O₄, MW: 295.26, mp 220-222° C.

5-nitro-2-amino-benzylamine hydrochloride

A solution of borane in THF (1 M, 840 ml) was added to a suspension of5-nitro-anthranilonitrile (120 g, 0.70 mol) in THF (1.2 L) under N₂ at0° C. The mixture was stirred for 2 hours at r.t. After cooling at 0°C., absolute EtOH (400 ml) was added, and HCl was bubbled through thesolution. The mixture was concentrated under reduced pressure and theresidue was triturated with ethanol, then with diisopropyl ether. Theobtained solid was dried in vacuum to give the titled product (140 g,98.6% yield). C₇H₉N₃O₂.HCl, MW: 203.63. TLC (CHCl₃:MeOH:H₂O:NH₃85:25:2:1) Rf=0.3.

Example 4 [2-(benzofuran-5-yl)-6-(1H-imidazol-1-yl)]quinazolinedihydrochloride

This compound was synthesized in 20% yield starting from6-amino-2-(5-benzofuran)-quinazoline, according to the proceduredescribed in example 3 for[2-(1,3-benzodioxol-5-yl)-6-(1H-imidazol-1-yl)]quinazoline. C₁₉H₁₂N₄O.2HCl; MW: 385.25; mp 284.7-285.1° C.; ¹H NMR (DMSO-d6) 10.00 (s, 1H),9.78 (s, 1H), 8.90 (s, 1H), 8.71 (d, 1H), 8.58 (d, 1H), 8.47 (m, 2H),8.29 (d, 1H), 8.10 (d, 1H), 8.02 (s, 1H), 7.78 (d, 1H), 7.15 (s, 1H); IR(KBr) 3399, 3097, 1614; TLC (CHCl₃:MeOH 9:1) Rf=0.38.

6-amino-2-(5-benzofuran)-quinazoline

This compound was synthesized in 59% yield starting frombenzofurane-5-carboxylic acid, according to the procedure described inexample 3 for the synthesis of6-amino-2-(1,3-benzodioxol-5-yl)-quinazoline. ¹H NMR (DMSO-d6) 9.31 (s,1H), 8.77 (s, 1H), 8.48 (dd, 1H), 8.06 (d, 1H), 7.68-7.80 (m, 2H), 7.41(dd, 1H), 7.10 (d, 1H), 6.93 (d, 1H); TLC (tol/AcOEt 7/3) Rf=0.35.

Synthesis of 6-nitro-2-(5-benzofuran)-quinazoline

This compound was synthesized in 76% yield, according to the proceduredescribed in example 2 for the synthesis of6-nitro-2-(1,3-benzodioxol-5-yl)-quinazoline. TLC (tol/AcOEt 7/3)Rf=0.80; mp. 293-7° C.

Example 5[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(1H-imidazol-1-yl)quinazoline

This compound was synthesized in 25% yield, according to the proceduredescribed in example 3 for[2-(1,3-benzodioxol-5-yl)-6-(1H-imidazol-1-yl)]quinazoline. C₁₉H₁₄N₄O₂,MW: 330.35; mp 131.5-131.9° C.; ¹H NMR (DMSO-d6) 9.64 (s, 1H), 8.49 (s,1H), 8.32-8.43 (m, 2H), 8.18 (s, 1H), 8.03-8.13 (m, 2H), 7.97 (d, 1H),7.21 (s, 1H), 7.04 (d, 1H), 4.34 (s, 4H); IR (KBr) 1555, 1507, 1286; TLC(CHCl₃:MeOH 9:1) Rf=0.38.

6-amino-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-quinazoline

This compound was synthesized in 67% yield, according to the proceduredescribed in example 3 for6-amino-2-(3,4-methylendioxy-phenyl)-quinazoline. C₁₆H₁₃N₃O₂, MW:279.30. mp 179.4-181.6° C.; ¹H NMR (DMSO-d6) 9.24 (s, 1H), 7.92-7.98 (m,2H), 7.72 (d, 1H), 7.38 (dd, 1H), 6.89-6.99 (m, 2H), 5.91 (s, 2H), 4.31(s, 4H); IR (KBr) 1555, 1507, 1286; TLC (CHCl₃/MeOH 9/1) Rf=0.65.

6-nitro-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-quinazoline

This compound was synthesized in 70% yield, according to the proceduredescribed in example 3 for6-nitro-2-(3,4-methylendioxy-phenyl)-quinazoline. C₁₆H₁₁N₃O₄, MW: 309,28; mp: 263-265; TLC (tol/AcOEt 7/3) Rf=0.80.

Example 6 [2-(3,4-dichlorophenyl)-6-(1H-imidazol-1-yl)]quinazoline

This compound was synthesized in 32% yield, starting from6-amino-2-(3,4-dichloro-phenyl)-quinazoline (prepared as described inEP1571142), according to the procedure described in example 3 for[2-(1,3-benzodioxol-5-yl)-6-(1H-imidazol-1-yl)]quinazoline. C₁₇H₁₀Cl₂N₄,MW: 341.20; mp 131.5-131.9° C.; ¹H NMR (DMSO-d6) 9.70 (s, 1H), 8.41-8.66(m, 4H), 8.22 (d, 1H), 7.98 (s, 1H), 7.82 (m, 2H), 7.21 (s, 1H); IR(KBr) 1578, 1548, 1500; TLC (CHCl₃:MeOH 9:1) Rf=0.41.

Example 7 [2-[(4-benzyloxy)phenyl-6-(1H-imidazol-1-yl)]quinazolinedihydrochloride

This compound was synthesized in 44% yield, starting from6-amino-2-(4-benzyloxy-phenyl)-quinazoline, according to the proceduredescribed in example 3 for[2-(1,3-benzodioxol-5-yl)-6-(1H-imidazol-1-yl)]quinazoline. The freebase was converted to the hydrochloride salt by treating its methanolsuspension with methanol/HCl and evaporating. The solid was trituratedin MeCN and dried i.v. to give the titled compound. C₂₄H₁₈N₄O.2HCl, MW:451.36; ¹H NMR (DMSO-d6) 9.81 (s, 1H), 8.02-8.96 (m, 7H), 7.21-7.52 (m,8H), 5.24 (s, 2H) mp 170° C.; IR (KBr) 3399, 2925, 1603, 1512, 1259; TLC(CHCl₃:MeOH 9:1) Rf=0.30.

Pharmacological Evaluation of the Compounds of the Invention

The efficacy of the compounds of Formula (I) for the treatment ofinflammatory and neuropathic pain along with inflammatory relateddisorders has been determined using the following in vitro assays and invivo animal models.

Compounds of the invention are not effective in inhibiting cycloxygenaseenzymes (COX-1 and COX-2), since they have been proven not to beeffective up to 10⁻⁵ M concentration, in standard in vitro test eitherfor COX-1 or for COX-2 enzyme inhibition. Furthermore compounds of theinvention are not effective in inhibiting nitric oxide synthase enzymes,since they have been proven not to be effective up to 10⁻⁵ Mconcentration, in standard in vitro test for iNOS and nNOS enzymeinhibition. Accordingly, the compounds of the invention are not actingas classical COX or iNOS enzyme inhibitors.

The compounds of the invention have been found effective in interferingwith COX-2 and cytokines production, in several cell lines; examples ofthese effects are reported in Table 3, for COX-2 and IL-1β and IL-6cytokines, in IL-1 stimulated human chondrosarcoma cell line.

TABLE 3 Inhibition (%) Inhibition Inhibition Concentration of COX-2 (%)of (%) of IL-6 Compound (μM) production IL-1 production productionExample 1 0.3 20 10 35 Example 3 0.3 35 20 20 1 64 15 35 10 75⁽¹⁾ 40 NAExample 5 0.3 50 20 NE 1 60 30 NE 10 70 40 35 ⁽¹⁾IC₅₀ is 0.63 ± 0.24 μM.

To this cytokine modulator property can be ascribed completely or inpart the anti-inflammatory and striking analgesic properties displayedby the compounds of the invention in in vivo models of inflammation andpain.

The interplantar injection of Zymosan-induced mechanical hyperalgesiawas used as a model of inflammatory pain (Meller, Neuropharmacology,1994, 33, 1471-1478). In this model, typically a male Sprague-Dawley orWistar rat (200-250 g) receives an interplantar injection of 3 mg/100 μlzymosan into one hind paw. A marked inflammation occurs in this hindpaw. Drugs are administered orally for evaluation of efficacy, 30 min.before the inflammatory insult. The hyperalgesia induced by zymosanadministration was evaluated using the Randall-Selitto method (Arch.Int. Pharmacodyn., 1957, 111, 409). The quantitation of the analgesiceffect is achieved by an analgesimeter, which consist in applying to theinflamed paw an increasing weight (from 130-140 g up to 500 g). Thedifference in the mechanical pain threshold between the basal value(generally 230-250 g) and the one tolerated by the animals treated withthe drug, determined 4 hours after the inflammatory challenge, isdefined as mechanical hyperalgesia. Mechanical hyperalgesia is expressedfor the compounds of the invention as ED₅₀, which is the dose of theadministered compound able to increase the pain threshold by 50% incomparison with the group of control animals. The corresponding ED₁₀₀,representing the dose able of reducing of 100% the pain threshold, canbe calculated for those cases where there is a linear dose-responserelationship. In vivo anti-inflammatory effect exerted by the compoundof the invention can be assessed in the same Zymosan inducedinflammation test described above, by measuring the volume of the oedemainduced by the inflammatory agent. The oedema was evaluated as theincrease in the volume of the Zymosan injected paw within a time of 0-2hrs. The measurements of the variation of the oedema volume of the pawwere recorded using hydroplethysmometer, which consists of two plasticcuvettes containing a surfactant liquid, the larger one being used forimmersion of the paw, connected to the smaller one which contains atransducer capable of recording small displacements of the volume usedfor the measure. The paw is immersed in the cuvettes up to thetibiotarsal joint. The volume of the liquid displaced is proportional tothe extent of the inflammation. The efficacy of the compounds of theinvention in preventing oedema formation is expressed as ED₃₀, ismeasured 2 hours after the inflammatory challenge, and represents thedose able of reducing of 30%, the Zymosan induced paw volume increase incomparison to control animals (animals treated with Zymosan but treatedwith only distilled water instead of the testing compound). Thecorresponding ED₅₀, representing the dose able of reducing of 50% theZymosan induced paw volume increase, can be calculated for those caseswhere there is a linear dose-response relationship. In both theexperiments, for each test compound, at least three doses were used,with 10 animals per group. Compounds of the invention were tested at 10,20 and 40 mg/Kg.

The performance of representative compounds of Formula (I), in the testsdescribed above, is summarized for both the analgesic effect and theanti-inflammatory effect in Table 4, where the activity of the compoundsof the invention is compared with the performance in the same test ofwell known standards. Representative compounds of the inventiondemonstrated efficacy superior or comparable to the standards both in atest of analgesia and for anti-inflammatory effects. In addition,compounds of the invention did not display ulcerative side effectscomparable to the ones displayed by Nimesulide, even at the higher dosestested.

TABLE 4 Analgesia (mg/Kg) Oedema Reduction (mg/Kg) Compound ED₅₀ ED₁₀₀ED₃₀ ED₅₀ Example 1 6.5 10 7.3 97 Example 3 2.8 5 172 NC Celecoxib 91172 13.8 644 Tramadol 25.7 405 NE NE Nimesulide 7.4 161 0.5 33.4 NE:not effective; NC: not computable

Analgesic activity of the compounds of Formula (I) can be furtherevaluated in an animal model of chronic inflammatory pain. Sinceclinically, inflammatory pain is most often associated with chronicconditions such as arthritis and chronic lower back pain, where anyinflammation or plastic neuronal change in the peripheral and centralnervous system would have been occurring for long time, chronic animalparadigms in which the inflammatory insult has had time to inducecentrally mediate changes, may result more predictive. The originalmodel of chronic inflammatory pain was based on injection ofinflammatory mediator (adjuvant) into the base of the tail in rats. As aconsequence of this treatment, a polyarthritis comprising profoundinflammation and hyperalgesia initially at the site of the injectionoccurs. However, due to T-cell mediated hypersensivity reaction, thedisease develops, in a couple of weeks, in multiple joint involvementand subsequent lesions to eyes, ears, nose and genitals. These globaleffects are not reflecting those clinically observed in commonpathologies characterized by chronic inflammatory pain. More recently,it was shown how the use of Complete Freund's Adjuvant (CFA;Mycobacterium tuberculosis) as triggering agent for the inflammatoryresponse along with the use of an appropriate protocol can give rise toa more suitable model. CFA-induced prolonged inflammation has been usedextensively in studies of behavioral pain response (K. Walker, Mol MedToday, 1999, 5, 319-321) since it has been considered also suitable forstudying involvement of neuronal plasticity in chronic pain (R. SharifNaeini, Eur. J. Neuroscience, 2005, 22, 8, 2005-2015). Experiments areperformed as described in the literature (C. J. Woolf, Br. J. ofPharmacology, 1997, 121, 417-424); 8 rats were used for each group, eachproduct was tested at three doses (3, 10, 30 mg/kg), the products wereadministered i.p., 24 hours after the interplantar challenge, and theanalgesic activity was measured starting from the 24 hours following thechallenge. In Table 5, results obtained in the CFA model, forrepresentative compounds of Formula (I) are listed in comparison toPiroxicam, a recognized standard. Analgesic effect is assessed using thesame equipment as before described for the Randall-Selitto model,results are reported as maximum percent effect (MPE) which representsthe difference (%) in pain threshold between the animals treated withthe drug and the controls that received only the vehicle (reduction ofthe nociceptive effect, due to paw loading with increasing weight, incomparison to controls which received CFA treatment). 100% protectionmeans that the animal treated with the compound and CFA can tolerate thesame stimulus (weight) as the control animal which has not received CFAtreatment. MPE higher than 100% mean that the animal treated with thecompound and CFA can tolerate stimuli (weight) higher than the controlanimals, which has not received CFA treatment (hypoalgesia). From theMPE data at 0.5 hrs, the doses yielding a protection of 50% (ED₅₀) and100% (ED₁₀₀) have been calculated.

TABLE 5 CFA Dose MPE MPE MPE ED₅₀ ED₁₀₀ Com- mg/ 0.5 MPE 3 MPE 24 0.5hrs. pound kg hrs. 1.5 hrs. hrs. 6 hrs. hrs. mg/kg Example 1 3 52 4 NENE NE 5.5 9.6 10 67 63 29 22 5 30 367 368 321 239 60 Example 3 3 54 9032 5 NE 2.7 4.7 10 216 188 85 23 3 30 344 198 101 49 41 Piroxicam 30 102111 54 24 38 NC NC NE: Not Effective; NC: Not Calculable

The compounds of the invention demonstrated also in this test apronounced and long lasting analgesic effect, at doses of 10 and 30mg/Kg, being the highest dose characterized with a remarkablehypoalgesic effect. The calculated ED₅₀ and ED₁₀₀ values were lower than10 mg/kg. At this dose the representative compounds are much moreeffective than Piroxicam, the reference standard.

Painful diabetic neuropathy is one of the most common complications ofinsulin-dependent diabetes in man; in particular, diabetes can beassociated with neuropathic pain which fails to be treated by classicalanalgesics. Streptozotocin (STZ)-induced diabetes in the rat has beenincreasingly used as a model of painful diabetic neuropathy to assessthe efficacies of potential analgesic agents (C. Courteix, Pain 1993,53, 81-8). The compounds of the invention were tested for efficacy inreducing mechanical hyperalgesia associated with STZ-induced diabetes inthe rat, according to the experimental model as described by theliterature. Diabetes was produced with the injection of a single dose(75 mg/Kg i.p.) of STZ. In the following four weeks after the inductionof diabetes the clinical symptoms (weight, body and skin temperature,motility and hyperglycemia) progressively developed by the animals, arestrictly monitored. After four weeks, the scores obtained in diabeticrats to various pain stimuli (in particular mechanical stimuli) weregreater than those in normal rats, indicating hyperalgesia. Thehyperalgesia induced by diabetes was evaluated using the Randall-Selittomethod as above described, and quantitated using the analgesimeter. Alsoin this case, the difference in the mechanical pain threshold betweenthe basal value (generally 230-250 g) and the one tolerated by theanimals treated with the drug, is defined as mechanical hyperalgesia.The compounds of the invention were administered i.p. (solution, Tween80, 10% in saline) at different doses, and mechanical hyperalgesia wasmeasured at the reported time, as maximum percent effect (MPE) whichrepresents the difference (%) in pain threshold between the animalstreated with the drug and the controls that received only the vehicle,compared with the weight borne by naïf non-diabetic controls. A 100%protection means that the diabetic animals treated with the compound cantolerate the same stimulus (weight) as the naïf non-diabetic animals.MPE higher than 100% means that the diabetic animal treated with thecompound can tolerate stimuli (weight) higher than the controlnon-diabetic animals (hypoalgesia).

In Table 6, the performance of representative compounds of Formula (I),in the above described model of neuropathic pain, is compared with someknown pharmacological standards used for the clinical treatment of thispathology. In particular, from the MPE data at 0.5 hrs, the dosesyielding a protection of 50% (ED₅₀) and 100% (ED₁₀₀) have beencalculated.

TABLE 6 Neuropathic Pain Dose ED₅₀ ED₁₀₀ mg/ MPE MPE MPE MPE 0.5 hrsCompound kg 0.5 hrs. 1.5 hrs. 3 hrs. 6 hrs. mg/kg Example 1 3 24 NE NENE 5.5 9.6 CR4056 10 41 68 NE NE 30 236 225 171 34 Example 3 3 73 88 5024 2.9 5.3 CR4115 10 141 143 98 49 30 283 273 263 264 Gabapentin 10 NENE NE NE NC NC 30 NE NE NE NE 100 NE NE NE NE 300 NE NE NE NEAmitriptyline 3 44 40 5 NE NC NC 10 68 77 NE NE 30 65 69 23 NE Tramadol3 26 53 7 NE 10.9 251 10 58 48 27 NE 30 54 64 23 NE 50 81 60 43 NE NE:not effective; NC = not calculable; *) extrapolated value

Representative Compounds of Formula I demonstrated to be quiteeffective, especially at the doses of 30 mg/kg (i.e. protection higherthan 100%), with ED₅₀ and ED₁₀₀ values lower than 10 mg/kg, as in theZymosan and CFA tests. On the contrary, all of the tested standardsexhibited a much lower efficacy, if any, in this paradigm. In fact, anED₅₀ value was calculable only for tramadol (for this standard the ED₁₀₀was only extrapolated from a dose-response curve approaching the 100%protection).

Pharmaceutical Compositions

Compounds of Formula I can be used in the manufacture of a suitablemedication for the therapeutic treatment of pain and inflammatoryrelated disorders. Especially for treatment of chronic pain disordersand immune-driven inflammatory events, which are a significant cause ofmany chronic inflammatory diseases where prolonged inflammation causestissue destruction and results in extensive damage.

Accordingly, appropriate pharmaceutical composition of compounds ofFormula (I), their salts and solvates thereof can be used for thetreatment of acute and chronic pain, including but not limited toinflammatory pain and associated hyperalgesia and allodynia,osteoarthritis pain, postoperative pain, visceral pain, pain associatedwith cancer, trigeminal neuralgia, acute herpetic and post herpeticneuralgia, neuropathic pain, diabetic neuropathy.

In addition, appropriate pharmaceutical composition of compounds ofFormula (I), their salts and solvates thereof, can be used for thetreatment of immune-driven inflammatory events including but not limitedto arthritis, rheumatoid arthritis and osteoarthritis, inflammatorydisorders of the gastrointestinal tract such as inflammatory boweldisease (IBD), ulcerative colitis, Crohn's disease (CD), inflammatoryurinary bladder disorders, inflammatory disorders of the respiratorytract chronic obstructive pulmonary disease (COPD) and asthma, postoperative inflammatory complications, inflammatory eyes disorders,systemic lupus erythematosus, skin diseases such as eczema, psoriasisand dermatitis.

In addition, appropriate pharmaceutical composition of compounds ofFormula (I), their salts and solvates thereof, can be used for thetreatment of cancer, including but not limited to: colon cancer,multiple myeloma, breast, cervical, prostate and lung cancer.

The compounds of the present invention may be administered orally,parenterally or topically, in a pharmacological effective amount. Theterm parenteral used herein includes intravenous, intramuscular,subcutaneous, intra-dermal and intra-articular.

For all methods of treatment herein discussed for the compounds ofFormula (I), the daily oral dosage regimen will preferably be from about0.1 to about 20 mg/Kg of total body weight. It will also be recognisedby one of skill in the art that the optimal quantity and spacing ofindividual dosages of a compound of Formula (I) will be determined bythe nature and extent of the condition being treated.

This invention also relates to a composition suitable for the treatmentof the above diseases, containing a pharmaceutically effective amount ofa compound of Formula (I), its salts, solvates and prodrugs thereof andits pharmaceutically acceptable carrier or diluent.

In order to use a compound of Formula (I) in therapy, it will normallybe formulated into a dosage form in accordance with conventional methodsof pharmacy and current guidelines and relevant good laboratory andmanufacturing practices.

The preferred route of administration for the compounds of the inventionis oral. The compounds of the invention can be formulated in a widevariety of oral dosage forms, such as capsules, tablets, pills, powdersand dispersible granules. Suitable carriers can be one or moresubstances which may also act as diluents, flavouring agents,solubilizer, lubricants, suspending agents, binders.

Suitable carriers include but are not limited to magnesium carbonate,magnesium stearate, talc, lactose, pectin, dextrin, starch,methylcellulose, sodium carboxymethyl cellulose, cocoa butter and thelike. Techniques used to prepare oral formulations are the conventionalmixing, granulation and compression or capsules filling. Other formssuitable for oral administration include emulsions, syrups and aqueoussolutions. Emulsions can be prepared using emulsifying agents forexample lecithin, propylene glycol or sorbitan monooleate. Aqueoussolutions can be prepared by dissolving the active component in waterand adding suitable colorants, flavours, stabilising agents.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection or by continuous infusion) as acomposition with suitable carriers including aqueous vehicles solutions(i.e.: saline, dextrose) or and/or oily emulsions. The drug product maybe presented in unit dose forms, for example in ampoules or pre-filledsyringes.

Formulation suitable for topical administration include liquid orsemi-liquid preparations suitable for the penetration through the skin(e.g.: liniments, lotions, ointments, creams and pastes) and dropssuitable for administration to the eyes.

1. A compound of Formula (I):

wherein: X is a nitrogen atom; W is independently selected from an arylgroup or an heteroaryl group of Formula II:

when W is an aryl group, it is an unsubstituted phenyl or phenylsubstituted with one or more substituents independently selected fromhalogen (—F, —Cl, —Br), trifluoromethyl (—CF₃), alkyl, hydroxyl (—OH),alkoxy, trifluoromethoxy (—OCF₃), cyano (—CN), carboxamido (—CONHR₃ or—NHCOR₃ or —CONR₂R₃), carbonyl (—CO—R₃), alkylthio (—SR₃), sulfinyl(—SOR₃) and sulfonyl (—SO₂R₃), wherein R₂ and R₃ groups are as definedbelow; when W is an heteroaryl group of Formula II, it is abenzocondensed -5 or -6 membered heterocycle, wherein: Z and Y areindependently selected from: an oxygen atom (—O—), a sulphur atom (—S—),or the groups: —SO₂—, —CHR₃—, —CR₃═, —NH—, —N═; Q is independentlyselected from the groups: —CHR₃—, —CH═, —CR₃═, —CHR₃—CH₂—; provided thatthe combination of Y, Z, Q groups give rise to: 1,3-benzodioxole,1,3-benzodithiol, benzofuran, 2,3-dihydrobenzofuran, benzothiophene,2,3-dihydrobenzothiophene, 2,3-dihydrobenzothiophene S,S-dioxide,indole, 2,3-dihydroindole, benzimidazole, benzoxazole, benzothiazole,2H-3,4-dihydrobenzopyran, 2H-3,4-dihydrobenzothiopyran,2H-3,4-dihydrobenzothiopyran S,S-dioxide, 2,3-dihydro-[1,4]-benzodioxine(1,4-benzodioxan), 2,3-dihydro-[1,4]-benzothiazine,2,3-dihydro-[1,4]-benzothiazine S,S-dioxide,2,3-dihydro-[1,4]-benzoxazine; R1 is independently selected fromhydrogen (—H) or C₁-C₄ alkyl or hydroxymethyl (—CH₂OH), aminomethyl(—CH₂NH₂), dimethylaminomethyl (—CH₂NMe₂), trifluoromethyl (—CF₃); theC₁-C₄ alkyl group is a linear or branched hydrocarbon chain; providedthat in compounds of Formula (I) not more than two R1 groups aresimultaneously C₁-C₄ alkyl or trifluoromethyl (—CF₃) and only one R1group is hydroxymethyl (—CH₂OH), aminomethyl (—CH₂NH₂) ordimethylaminomethyl (—CH₂NMe₂); R₂ is independently selected from C₁-C₆alkyl or aryl; C₁-C₆ alkyl is a linear or branched, saturated orunsaturated C₁-C₆ hydrocarbon chain, optionally substituted with anaryl, aryl being as defined above; R₃ is independently selected fromhydrogen, C₁-C₆ alkyl and aryl; C₁-C₆ alkyl is a linear or branched,saturated or unsaturated C₁-C₆ hydrocarbon chain optionally substitutedwith an aryl, aryl being as defined above, or a pharmaceuticallyacceptable salt thereof.
 2. The compound of Formula (I) according toclaim 1, in which the substituent X is a nitrogen atom and W is anunsubstituted phenyl or phenyl substituted with one or more substituentsindependently selected from: halogen (—F, —Cl, —Br), trifluoromethyl(—CF₃), alkyl, hydroxyl (—OH), alkoxy, trifluoromethoxy (—OCF₃), cyano(—CN), carboxamido (—CONHR₃ or —NHCOR₃ or —CONR₂R₃), carbonyl (—CO—R₃),alkylthio (—SR₃), sulfinyl (—SOR₃) and sulfonyl (—SO₂R₃), wherein R₂ andR₃ are as defined in claim
 1. 3. The compound of Formula (I) accordingto claim 1, in which the substituent X is a nitrogen atom and W is anheteroaryl group of Formula II, according to claim 1, whereincombination of Y, Z, Q groups give rise to: 1,3-benzodioxole,benzofuran, 2,3-dihydrobenzofuran, 2H-3,4-dihydrobenzopyran,2,3-dihydro-[1,4]-benzodioxine (1,4-benzodioxan).
 4. The compound ofFormula (I) according to claim 1, in which the substituent X is anitrogen atom and W is an heteroaryl group of Formula II, according toclaim 1, wherein combination of Y, Z, Q groups give rise to:1,3-benzodithiol, benzothiophene, 2,3-dihydrobenzothiophene,2,3-dihydrobenzothiophene S,S-dioxide, 2H-3,4-dihydrobenzothiopyran,2H-3,4-dihydrobenzothiopyran S,S-dioxide.
 5. The compound of Formula (I)according to claim 1, in which the substituent X is a nitrogen atom andW is an heteroaryl group of Formula II, according to claim 1, whereincombination of Y, Z, Q groups give rise to: indole, 2,3-dihydroindole,benzimidazole, benzoxazole, benzothiazole,2,3-dihydro-[1,4]-benzothiazine, 2,3-dihydro-[1,4]-benzothiazineS,S-dioxide, 2,3-dihydro-[1,4]-benzoxazine.
 6. The compound according toclaim 1 in the form of a pharmaceutically acceptable salt selected fromthe group consisting of hydrochloride, hydrobromide, hydrogensulphateand sulphate, maleate, fumarate, oxalate, methanesulfonate, succinate,ascorbate, tartrate.
 7. A pharmaceutical composition comprising, atleast one compound according to claim 1, and further comprisingpharmaceutically inactive ingredients selected from the group consistingof vehicles, binders, flavourings, sweeteners, disaggregants,preservatives, humectants and mixtures thereof.
 8. A pharmaceuticalcomposition comprising, at least one of the compounds according to claim1, for parenteral use (intravenous, intramuscular, subcutaneous,intradermal, intra-articular), and further comprising pharmaceuticallyinactive ingredients selected from the group consisting of aqueousvehicles solutions, oily emulsions and mixtures thereof.